1. The Field of the Invention
The present invention relates to lamotrigine immunodiagnostic reagents and protocols. More particularly, the present invention relates to lamotrigine, lamotrigine analogs, immunogens and antigens prepared from lamotrigine analogs, antibodies prepared from lamotrigine-based immunogens, and methods of making and using the same.
2. The Related Technology
Lamotrigine, chemically represented as 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine and shown below, is an anti-epileptic drug (“AED”) of the phenyltriazine class, and is chemically unrelated to existing AEDs. Lamotrigine is the active ingredient in LAMICTAL® (Glaxo Wellcome), an FDA-approved drug used for anti-epileptic treatment as well as for treatment of the psychiatric disorders, such as bipolar disease.

Epilepsy is brain function disorder that results in repeated seizures. Lamotrigine has been shown to have a broad spectrum of clinical efficacy, and is effective in treating and/or preventing partial seizures, primary and secondarily generalized seizures, absence seizures, and drop attacks associated with Lennox-Gastaut syndrome.
It is well known that various drugs such as AEDs, can have different pharmacokinetic and/or pharmacodynamic profiles in different patient populations, which results in the therapeutic drug monitoring (“TDM”) of AEDs to be vitally important. One goal of a TDM program is to optimize a patient's clinical outcome by managing and/or optimizing a medication regimen with the assistance of determining drug concentrations at various times. Accordingly, the drug dose and regimen can be modulated for a single patient or patient population based on TDM.
Several characteristics of lamotrigine suggest there is a clinical need to individualize patient therapy by use of TDM. It has been suggested that there are large inter-individual variations in dose versus serum concentrations in patients, and pharmacokinetic variability plays a major role in the lamotrigine dosage requirements needed to achieve optimum serum concentrations.
It as been suggested that an appropriate range of optimal serum concentrations for lamotrigine would be 12 to 55 μmol/L in patients with refractory epilepsy. See Morris R G et al, Br J Clin Pharmacol; 46:547-51 (1998). In the responders (>50% seizure reduction), the median lamotrigine concentration was 31 μmol/L (range, 8-60 μmol/L) compared with 62 μmol/L (range, 31-60 μmol/L) in patients with side effects. As such, a target range of 10 to 60 μmol/L (2.54-15.24 μg/mL) is now suggested for lamotrigine. Thus, effective TDM can be used to predict dosing regimens that can obtain appropriate lamotrigine concentrations within the therapeutic index.
Many methods have been described for analyzing lamotrigine. Primarily, the methods include HPLC with ultraviolet (“UV”) detection. See, Fraser et al, Ther Drug Monitoring, 17:174-178, 1995; Lensmeyer et al, Ther Drug Monitoring, 19:292-300, 1997; Croci et al. Ther Drug Monitoring 23:665-668, 2001. In addition, a competitive binding enzyme immunoassay (ELISA) for the measurement of lamotrigine in sera has been reported. See, Sailstad et al, Ther Drug Monitoring, 13:433-442, 1991. However, such methods are impractical for commercial use due to, for example, long sample preparation time, long assay time, high cost, and labor-intensive procedures. Thus, a simple and fast analytical method for measuring lamotrigine plasma levels is needed for effective TDM, which immunoassay techniques are well suited for such analytical applications.
Immunoassay techniques have been developed to detect various drugs in biological samples and are well suited for such commercial analytical applications. Accordingly, immunoassays can be used to quickly assess the amount of a drug and/or drug metabolite in a patient's blood. Examples of immunoassays can include, but not limited to, homogeneous microparticle immunoassay (e.g., immunoturbidimetric) or quantitative microsphere system (“QMS®”), fluorescence polarization immunoassay (“FPIA”), cloned enzyme donor immunoassay (“CEDIA”), chemiluminescent microparticle immunoassay (“CMIA”), and the like.
Accordingly, it would be advantageous to have immunoassays configured to detect lamotrigine in a patient's blood, serum, plasma, and/or other biological fluids or samples. Additionally, it would be advantageous to have lamotrigine analogs for use in such immunoassays, and/or lamotrigine analog-based immunogens for use in producing anti-lamotrigine antibodies.